Nanotechnology is a multidisciplinary field involving the development of engineered devices at the atomic, molecular and macromolecular level, in the nanometer range (typically 1-100 nm). Recent advances in nanotechnology have raised exciting possibilities for the application of nanomaterials to biomedical imaging and the targeted delivery of drugs. We have recently developed a novel nanoparticle formulation with potent stimulatory effects on the formation of osteoblasts, the cells responsible for bone formation, and concomitant inhibitory effects on the formation of osteoclasts, the cells responsible for bone breakdown (resorption). This nanoparticle may have the potential to be developed into a powerful dual anticatabolic and proanabolic agent for the treatment of numerous osteoporotic diseases. However, before any reagent can be developed into a drug for use in humans it is imperative to understand the molecular and cellular mechanisms by which it regulates cell metabolism in order to assess its likely safety profile in vivo, and to understand potential toxic or non-specific side-effects on skeletal and non-skeletal cells. Our preliminary studies suggest that that this nanoparticle formulation achieves its stimulatory effects on osteoblasts, and inhibitory effects on osteoclasts, by a mechanism involving the suppression of the Nuclear Factor Kappa B (NF-kB) transcription factor. The NF-kB signal transduction pathway is established to be critical for production of bone resorbing osteoclasts in vitro and in vivo. By contrast, we and others have recently reported that the NF-kB pathway is potently inhibitory to osteoblastic differentiation and mineralization in vitro. Based on our preliminary data we hypothesize that this novel nanoparticle formulation inhibits osteoclast activity and stimulates osteoblast activity by suppressing the NF-kB signal transduction pathway. In Specific Aim 1 we propose to investigate the action of this nanoparticle on the NF-kB signal transduction pathway in differentiating osteoclast and osteoblast precursors. In Specific Aim 2 we will generate variants of the wild type nanoparticle possessing different physical and chemical properties including alterations to surface charge, surface decoration, and size, to determine which specific attributes are responsible for internalization entry into the cell, and biological action on the NF-kB pathway. Finally, in Specific Aim 3 we will evaluate the potential for this nanoparticle formulation to enhance bone mineral density and bone structure by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in mice in vivo. PUBLIC HEALTH RELEVANCE: Nanotechnology has the power to revolutionize medicine. We recently developed a nanoparticle capable of inhibiting bone breakdown, while simultaneously stimulating new bone formation. We now seek to fully investigate the action of this particle on bone cells, and test its capacity to enhance bone mass in vivo.